Feline Hypertrophic Cardiomyopathy: A Spontaneous Large Animal Model of Human HCM.

Hypertrophic cardiomyopathy (HCM) is a common disease in pet cats, affecting 10-15% of the pet cat population. The similarity to human HCM, the rapid progression of disease, and the defined and readily determined endpoints of feline HCM make it an excellent natural model that is genotypically and phenotypically similar to human HCM. The Maine Coon and Ragdoll cats are particularly valuable models of HCM because of myosin binding protein-C mutations and even higher disease incidence compared to the overall feline population. The cat overcomes many of the limitations of rodent HCM models, and can provide enhanced translation of information from in vitro and induced small animal models to human clinical trials. Physicians and veterinarians working together in a collaborative and interdisciplinary approach can accelerate the discovery of more effective treatments for this and other cardiovascular diseases affecting human and veterinary patients

Training Cognitive Control in Older Adults with the Space Fortress Game: The Role of Training Instructions and Basic Motor Ability

This study examined if and how cognitively healthy older adults can learn to play a complex computer-based action game called the Space Fortress (SF) as a function of training instructions [Standard vs. Emphasis Change (EC); e.g., Gopher et al., 1989] and basic motor ability. A total of 35 cognitively healthy older adults completed a 3-month SF training program with three SF sessions weekly. Twelve 3-min games were played during each session. Basic motor ability was assessed with an aiming task, which required rapidly rotating a spaceship to shoot targets. Older adults showed improved performance on the SF task over time, but did not perform at the same level as younger adults. Unlike studies of younger adults, overall SF performance in older adults was greater following standard instructions than following EC instructions. However, this advantage was primarily due to collecting more bonus points and not – the primary goal of the game – shooting and destroying the fortress, which in contrast benefited from EC instructions. Basic motor ability was low and influenced many different aspects of SF game learning, often interacted with learning rate, and influenced overall SF performance. These findings show that older adults can be trained to deal with the complexity of the SF task but that overall SF performance, and the ability to capitalize on EC instructions, differs when a basic ability such as motor control is low. Hence, the development of this training program as a cognitive intervention that can potentially compensate for age-related cognitive decline should consider that basic motor ability can interact with the efficiency of training instructions that promote the use of cognitive control (e.g., EC instructions) – and the confluence between such basic abilities and higher-level cognitive control abilities should be further examined

Aberrant migration and surgical removal of a heartworm (Dirofilaria immitis) from the femoral artery of a cat.

A cat was evaluated for an acute-onset of right pelvic limb paresis. Thoracic radiographs revealed normal cardiac size and tortuous pulmonary arteries. Abdominal ultrasound identified a heartworm (HW) extending from the caudal abdominal aorta into the right external iliac artery and right femoral artery. The cat was HW-antigen positive. Echocardiography revealed a HW within the right branch of the main pulmonary artery and evidence of pulmonary hypertension. An agitated-saline contrast echocardiogram revealed a small right to left intracardiac shunt at the level of the atria. Surgical removal of the HW was performed with no substantial postoperative complications. There was return of blood flow and improved motor function to the limb. The cat remains mildly paretic on the affected limb with no other clinical signs

A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs

Familial subvalvular aortic stenosis (SAS) is one of the most common congenital heart defects in dogs and is an inherited defect of Newfoundlands, golden retrievers and human children. Although SAS is known to be inherited, specific genes involved in Newfoundlands with SAS have not been defined. We hypothesized that SAS in Newfoundlands is inherited in an autosomal dominant pattern and caused by a single genetic variant. We studied 93 prospectively recruited Newfoundland dogs, and 180 control dogs of 30 breeds. By providing cardiac screening evaluations for Newfoundlands we conducted a pedigree evaluation, genome-wide association study and RNA sequence analysis to identify a proposed pattern of inheritance and genetic loci associated with the development of SAS. We identified a three-nucleotide exonic insertion in phosphatidylinositol-binding clathrin assembly protein (PICALM) that is associated with the development of SAS in Newfoundlands. Pedigree evaluation best supported an autosomal dominant pattern of inheritance and provided evidence that equivocally affected individuals may pass on SAS in their progeny. Immunohistochemistry demonstrated the presence of PICALM in the canine myocardium and area of the subvalvular ridge. Additionally, small molecule inhibition of clathrin-mediated endocytosis resulted in developmental abnormalities within the outflow tract (OFT) of Xenopus laevis embryos. The ability to test for presence of this PICALM insertion may impact dog-breeding decisions and facilitate reduction of SAS disease prevalence in Newfoundland dogs. Understanding the role of PICALM in OFT development may aid in future molecular and genetic investigations into other congenital heart defects of various species

Adaptive Optics Imaging of the AU Microscopii Circumstellar Disk: Evidence for Dynamical Evolution

We present an H-band image of the light scattered from circumstellar dust around the nearby (10 pc) young M star AU Microscopii (AU Mic, GJ 803, HD 197481), obtained with the Keck adaptive optics system. We resolve the disk both vertically and radially, tracing it over 17-60 AU from the star. Our AU Mic observations thus offer the possibility to probe at high spatial resolution (0.04" or 0.4 AU per resolution element) for morphological signatures of the debris disk on Solar-System scales. Various sub-structures (dust clumps and gaps) in the AU Mic disk may point to the existence of orbiting planets. No planets are seen in our H-band image down to a limiting mass of 1 M_Jup at >20 AU, although the existence of smaller planets can not be excluded from the current data. Modeling of the disk surface brightness distribution at H-band and R-band, in conjunction with the optical to sub-millimeter spectral energy distribution, allows us to constrain the disk geometry and the dust grain properties. We confirm the nearly edge-on orientation of the disk inferred from previous observations, and deduce an inner clearing radius <=10 AU. We find evidence for a lack of small grains in the inner (<60 AU) disk, either as a result of primordial disk evolution, or because of destruction by Poynting-Robertson and/or corpuscular drag. A change in the power-law index of the surface brightness profile is observed near 33 AU, similar to a feature known in the profile of the beta Pic circumstellar debris disk. By comparing the time scales for inter-particle collisions and Poynting-Robertson drag between the two systems, we argue that the breaks are linked to one of these two processes.Comment: 17 pages, 7 figures, 1 table; accepted by Ap

No impact of polymorphism in the phosphodiesterase 5A gene in Cavalier King Charles Spaniels on pimobendan-induced inhibition of platelet aggregation response

Background: A variant in the canine phosphodiesterase (PDE) 5A gene (PDE5A: E90K) is associated with decreased concentrations of circulating cyclic guanosine monophosphate (cGMP) and response to PDE5 inhibitor treatment. Pimobendan is a PDE inhibitor recommended for medical treatment of certain stages of myxomatous mitral valve disease (MMVD) in dogs.Hypothesis: PDE5A:E90K polymorphism attenuates the inhibitory effect of pimobendan on in vitro platelet aggregation and increases basal platelet aggregation in Cavalier King Charles Spaniels (CKCS). Selected clinical variables (MMVD severity, sex, age, hematocrit, platelet count in platelet-rich plasma [PRP], and echocardiographic left ventricular fractional shortening [LV FS]) will not show an association with results.Animals: Fifty-two privately owned CKCS with no or preclinical MMVD.Methods: Using blood samples, we prospectively assessed PDE5A genotype using Sanger sequencing and adenosine diphosphate-induced platelet aggregation response (area under the curve [AUC], maximal aggregation [MaxA], and velocity [Vel]) with and without pimobendan using light transmission aggregometry. Dogs also underwent echocardiography.Results: Pimobendan inhibited platelet function as measured by AUC, MaxA, and Vel at a concentration of 10 mu M (P <.0001) and Vel at 0.03 mu M (P <.001). PDE5A:E90K polymorphism did not influence the inhibitory effect of pimobendan or basal platelet aggregation response.Conclusions and Clinical Importance: The PDE5A:E90K polymorphism did not influence in vitro basal platelet aggregation response or the inhibitory effect of pimobendan on platelet aggregation in CKCS. Dogs with the PDE5A:E90K polymorphism did not appear to have altered platelet function or response to pimobendan treatment

Angiotensin-converting enzyme activity and inhibition in dogs with cardiac disease and an angiotensin-converting enzyme polymorphism

OBJECTIVE The objective of this study was to evaluate angiotensin-converting enzyme (ACE) activity in dogs and with and without an ACE polymorphism in the canine ACE gene, before and after treatment with an ACE inhibitor. METHODS Thirty-one dogs (20 wild-type, 11 ACE polymorphism) with heart disease were evaluated with ACE activity measurement and systolic blood pressure before and after administration of an ACE inhibitor (enalapril). RESULTS Median pre-treatment ACE activity was significantly lower for ACE polymorphism dogs than for dogs with the wild-type sequence ( P=0.007). After two weeks of an ACE inhibitor, ACE activity was significantly reduced for both genotypes (wild-type, P&lt;0.0001; ACE polymorphism P=0.03); mean post-therapy ACE activity was no different between the groups. CONCLUSION An ACE polymorphism is associated with lower levels of ACE activity. Dogs with the polymorphism still experience suppression of ACE activity in response to an ACE inhibitor. It is possible that the genetic status and ACE activity of dogs may impact the response of dogs with this variant to an ACE inhibitor